Previous work in our laboratory has demonstrated that a human isolate of coxsackievirus B3 replicating in a selenium deficient animal develops specific viral mutations. These viral mutations result in increased virulence of the virus, allowing a normally avirulent virus to become virulent. These same specific stable mutations repeatedly evolve under conditions of nutritional deficiency. In addition, we have recently demonstrated that a nutritionally-deficient human population infected with coxsackievirus A9 (another human enterovirus) exhibited rapid and significant sequence divergence of this virus. Thus, we demonstrated for the first time that the nutritional status of both animals and humans can profoundly influence the genome of a viral pathogen, leading to a new viral strain. Our discovery that host nutritional status is a driving force for viral mutation/evolution, suggested a new area for research, namely the interaction of host nutrition and viral evolutionary processes. We believe that host nutritional status is an underappreciated factor in viral emergence, and that we possess both the laboratory models and the human isolates to make a substantial contribution to elucidating the behavior of virus populations in hosts with suboptimal nutrition. The ultimate, long-term goal of this research is to identify patterns of change in virus populations, on the molecular level, that will facilitate the ability to recognize and predict the emergence and spread of a new or altered pathogen. We propose that host nutritional status has been widely ignored as a driving force for viral evolution, despite the fact that new viral strains, and old viral strains with newly pathogenic properties, often occur in populations with widespread malnutrition. Thus, our studies provide a unique opportunity to understand the interaction between host nutrition and viral genome evolution. This grant is an interdisciplinary study involving the fields of nutrition, virology, evolutionary biology, and computational biology. Our model system will begin as a cell culture study to develop models of virus evolution which will then be tested by expanding into animal models. Finally, we will test the robustness of our models using viral isolates obtained from a human nutritional stress that resulted in viral mutation. PUBLIC HEALTH RELEVANCE: Emerging infectious diseases are a continuing threat to the world's population. Although many factors contribute to the emergence of new pathogens, including travel, global warming, introduction into new species, etc., nutritional status of the host has not been widely considered. This project is designed to understand how selenium nutritional status can impact changes in viral adaptation. The goal is to develop tools to predict outbreaks of emerging infectious diseases.